CaMKII-δ9在心脏缺血/再灌损伤及其修复中的作用与机制研究

心血管疾病严重威胁人类健康。心脏缺血/再灌（I/R）是引起心脏损伤最常见的原因之一，缺乏有效防治手段。申请者最近首次发现CaMKII-d9是人心脏中最主要的CaMKII-d可变剪切体，通过调节心肌细胞DNA损伤引起肥厚性心肌病，但其在心脏中的生理和病生理功能远未阐明。本研究希望对CaMKII-d9在心脏I/R损伤与修复中的作用与机制进行研究，包括：①CaMKII-d9是否能够通过促进心脏损伤、抑制心脏修复，介导心脏I/R引起的心肌重构和心衰；②CaMKII-d9介导心脏I/R损伤的病生理与分子机制是什么，尤其是其对心肌细胞死亡和再生的调节功能与机制；③能否通过腺相关病毒抑制CaMKII-d9，保护心脏I/R损伤，促进其修复，防治后续的心衰等疾病。据此，我们一方面希望系统研究CaMKII-d9在心脏疾病中的作用与机制，另一方面希望探索心脏I/R损伤及修复的调节机制，寻找其相关疾病的防治策略。

Cardiovascular disease is a serious threat to human health. Cardiac ischemia/reperfusion (I/R) is one of the most common causes of cardiac injury, which is still lack of effective therapy. Recently, for the first time, we found that CaMKII-d9 is the most important CaMKII-d splice variant in human heart, and is involved in hypertrophic cardiomyopathy through the induction of cardiomyocyte DNA damage. But the physiological and pathophysiological functions of CaMKII-d9 in the heart are far from clear. Here, we hope to investigate the role and mechanisms of CaMKII-d9 in cardiac I/R injury and repair. In details, ① Whether upregulation of CaMKII-d9 promotes I/R-induced cardiac injury and inhibits cardiac repair to mediate myocardial remodeling and heart failure. ② What are the pathophysiological and molecular mechanisms of CaMKII-d9-mediated cardiac I/R injury, especially its role and mechanism on cardiomyocyte death and regeneration. ③ Whether adeno-associated virus-mediated inhibition of CaMKII-d9 is able to protect cardiac I/R injury, promote its repair, and prevent subsequent heart failure and other diseases. Based on the above studies, we hope to not only systematically study the role and mechanism of CaMKII-d9 in heart diseases, but also explore the regulatory mechanism of cardiac I/R injury and repair, and find the prevention and treatment strategies of its related diseases.